Thursday, 31 December 2015

"This relatively small study of 111 pwMS demonstrates that with intermediate-term follow-up (mean of 8 years) the presence of Gd-enhancing, or active, lesions at baseline correlated with the subsequent number of relapses, but not with disability. Interestingly, only relapses, and not Gd-enhancing lesions, correlated with subsequent disability."

"This study suggests that the detection of Gd-enhancing lesions may not be the best predictor of outcome and that relapses are more important. This raises the issue of whether or not clinically-silent Gd-enhancing lesions are different to lesions associated with relapses. I have always said that if you take a narrow EDSS-view of disability then you are biasing the results in favour of symptomatic lesions, i.e. what the EDSS measures. What about what the EDSS does not measure; for example cognition, mood, vision, etc.? It would therefore be interesting to know if Gd-enhancing lesions correlated with more sensitive measures of hidden disabilities, in particular cognitive impairment."

"Within the paper there was a correlation between MRI T2 & T1 lesion loads, and brain volume and the PASAT (paced auditory serial addition test) a cognitive test. This data indicates that focal MS lesions (T2/white blobs & T1/black holes), which almost all start their life out as Gd-enhancing lesions, is correlated with cognitive impairment. Hence the results of this study are consistent with what we know about the pathology of MS lesions and the lack of correlation between baseline Gd-enhancing lesions and intermediate term disability can almost certainly be explained by methodological issues; a relatively small study (n=111), treatment effects (79% received a DMT, which affects outcomes), use of the EDSS as the primary disability measure (we know that the EDSS captures cognitive impairments poorly) and finally intermediate- (8 year) rather than long-term (>= 15 years), follow-up."

"Will these results change how we use the baseline MRI in clinical practice? No. High baseline lesion load (T2), the presence of T1 black holes, posterior fossa and spinal cord lesions, brain atrophy and Gd-enhancing lesions at baseline will still be used to indicate a relatively poor prognostic profile."

BACKGROUND/PURPOSE: Contrast-enhancing lesions (CEL) on magnetic resonance imaging (MRI) are believed to represent inflammatory disease activity in multiple sclerosis (MS), but their relationship to subsequent long-term disability and progression is unclear, particularly at longer time periods such as 8-10 years.

METHODS: Between 1989 and 1994, 111 MS patients were seen at the National Institutes of Health for clinical evaluations and 3 monthly contrast-enhanced MRI scans. Of these, 94 patients were re-evaluated a mean of 8 years later (range 6.1-10.5 years) with a single MRI scan and clinical evaluation. CEL number and volume were determined at baseline and follow-up. The number of relapses was ascertained over the follow-up period and annualized relapse rates were calculated. Other MRI parameters, such as T2 hyperintensity volume, T1 volume, and brain parenchymal fraction, were also calculated.

RESULTS: While there was no direct correlation between CEL number or volume at baseline and disability status at follow-up, CEL measures at baseline did correlate with number of relapses observed in the subsequent years, and the number of relapses in turn correlated with subsequent disability as well as transition to progressive MS.

CONCLUSION: While number and volume of CEL at baseline do not directly correlate with disability in the longer term in MS, our data suggest that one route to disability involves relapses as a mediator variable in the causal sequence of MS progression from CEL to disability. Further studies using relapse as a mediator variable in a larger data set may be warranted.

Experimental autoimmune encephalomyelitis (EAE) is a widely-used rodent model for multiple sclerosis (MS), but a single model can hardly capture all features of MS. We investigated whether behavioral parameters in addition to clinical motor function scores could be used to assess treatment efficacy during score-free intervals in the relapsing-remitting EAE model in SJL/J mice. We studied the effects of the clinical reference compounds FTY720 (fingolimod, 0.5mg/kg/day) and dimethyl fumarate (DMF, 20-30mg/kg/day) on clinical scores in several rodent EAE models in order to generate efficacy profiles. SJL/J mice with relapsing-remitting EAE were studied using behavioral tests, including rotarod, gait analysis, locomotor activity and grip strength.

Prophylactic treatment with FTY720 prevented clinical scores in three of the four EAE rodent models: Dark Agouti (DA) and Lewis rats and C57BL/6J mice. Neither prophylactic nor late-therapeutic treatment with FTY720 reduced clinical scores or reversed deficits in the rotarod test in SJL/J mice, but we observed effects on motor functions and sociability in the absence of clinical scores. Prophylactic treatment with FTY720 improved the gait of SJL/J mice. DMF was tested in three EAE models and did not improve clinical scores at the dose used. These data indicate that improvements in behavioral deficits can occur in absence of clinical scores, which indicate subtle drug effects and may have translational value for human MS.

So we use animal models as a tool to predict response of drugs in MS so in this study they take Dimethyl fumarate and FTY720 and find that FTY720 (fingolimod) inhibits disease in EAE Dark Agouti (DA) and Lewis rats and C57BL/6J mice but not SJL mice, unless you do subtle behavioural tests. On the other hand DMF did not have an effect.

So first thing you have to say is that we know that fingolimod and slow release dimethyl fumarate work in MS and so if they don't work in EAE, then the models have no validity for their purpose and are of no use.

So I hear many of you say....yeah. EAE is rubbish and is useless!!!!

Yes we have to deal with this critisism everyday and this paper adds to this view. Therefore it is appropriate to comment.

However positive responses of both DMF and FTY720 in EAE would have both been part of the drug response to developing these drugs, so why the negative data?.

What about EAE in SJL mice and fingolimod why the failure? Is the SJL mouse strainrubbish to study drug effects?.....

Whilst I personally think it is pretty rubbish...not because it does not respond to FTY720, but because it gets too sick and its front and hind legs are affected (we would cull these animals as they can't get to food and water) and doesn't relapse with high enough frequency to be useful for drug testing (OK this is a personal preference and a little dig). What have other found?

I bet I could find loads of examples as contract research organisations that do contract drug testing and use fingolimod (FTY720) as the positive control, because it works in MS.

If you go to Novaritis and ask if it works in SJL mice, they would probably say, we like to see positive responses in more than one strain/species but you have to use the human equivalent dose to get an idea of whether it will work in humans. In this study they use 0.5mg/kg but the human equivalent dose is I believe 3mg/kg and this certainly works in ABH mice, so was enough used early enough?

Now to DMF. In the human they us only a small dose of slow release material but it is used 2 times a day because it has terrible pharmacokinetics even with the slow release formulation and without it it would be many more timesadayand if you do not use the slow release formulation as made by Biogen it is even more rubbish and so to get any response you have to use bucket loads of the stuff. At once a day dose if you look at work done by Biogen they use 100-200mg/kg dimethyl fumarate to get any form of inhibition because of the poor pharmacokinetics of a drug, so if you pluck a dose say 30mg/kg out of the air it may not work.

Indeed, if you use lower doses that 100mg/kg/day you have to dose animals at least twice a day, which is a pain in the bum when you have to do weekend dosing. But indeed that is how it can work and we have done it in C57BL/6 mice recently.

So this shows the importance of doing a dose-response in animal experiments. Yes, it uses more animals but maybe it helps you get more sensible answers. So first you can read and find what companies who make the drug and others have used and there are ways to examine dose response without doing them in EAE.

However, too often we see one dose used in EAE experiments to give the perfect response. This no doubt leads to the over-estimation of success of a particulary drug as they have given more and more until it worked, generally we use ten times dilutions.

However when you get negative results, you need to find out why

So we move into 2016 and no doubt we will get some great animal work but this will be peppered with the usual guff that plagues basic science.

So we will no doubt have some more MD rants in the future.

But if referees actually read and implimented suggestions based on the ARRIVE guidelines there would be alot less unreproducible guff that we get to read.

Wednesday, 30 December 2015

Off-label prescribing; should it be one of our New Year's resolutions? #PoliticalSpeak #MSBlog #OffLabel

"On reflection one of the most important issues we have tried to address on this blog in 2015 is access to effective DMTs for people with MS (pwMS) who live in resource-poor settings. My personal experiences of what it is like to be a pwMS living in a resource-poor country remains the primary motivator for this policy initiative. Barts-MS plans to take this policy forward in 2016 with the help of several new partners."

"A part of the solution we have been promoting the use of off-label, cheaper, alternative DMTs to treat MS. The following is our Barts-MS essential off-label DMT list (click on each drug for more information):

We think there is enough direct, or indirect, efficacy and safety data to support the use of these drugs as DMTs in MS.""Interestingly, we have a lot of resistance to this policy from multiple sources; internally from within our University (Policy Unit), Pharma, colleagues (from both resource rich and poor countries), and even several of the MS Charities. Our policy unit feels that there is far too much inappropriate off-label prescribing in the world and that we should really stick to the policy of only prescribing on-label. Pharma as it challenges their business model. Colleagues in resource-rich countries feel the medicolegal risks of prescribing off-label are too high and can't be justified. Clinicians in resource-poor settings don't like double-standards; why should they apply lower standards to treating pwMS in their countries? Surely, pwMS in resource-poor countries should have access to the same DMTs with appropriate risk:benefit assessments to those living in richer countries? The MS Charities favour lobbying Pharma to make available licensed DMTs at a cheaper price to pwMS in resource poor countries. The latter solution exists in many other disease areas; why not in MS? I suspect there is still a perception that MS is a 'rich-country' disease and is too rare in developing countries to warrant a sponsored drug-access scheme. Herein lies the problem. MS is not only a rich-country disease, we are seeing increasing incidence rates across the developing world. We mustn't forget pwMS who live in these countries, they need our help. If we want to reduce the burden of MS across the world we need workable policies so that MSers living in resource-poor countries get access to the same health care and treatments as MSers living in the developed world."

"The New Year will therefore see us launch a new initiative to focus on MS issues that are unique and pertinent to the pwMS living in developing countries and/or in resource poor settings; the latter includes refugees, illegal immigrant populations and possibly the medically uninsured living in developed countries. If you are a healthcare professional (HCP) looking after pwMS in these environments and want to help and be part of this initiative please do not hesitate to contact us. As will all policy initiatives the more people who get involved the better. We need volunteers!""We still have an open survey running to see how much support we have for the off-label prescribing component of our policy. When I last checked the results over 80% of you were supportive of our efforts. Do you still feel this way?"
Loading..."Let's make 2016 the year of hope and effective treatment options for all people living with MS. Happy New Year!"CoI: multiple

Multiple sclerosis is an autoimmune disease that affects the white matter of the central nervous system and involves inflammation and demyelination. The recent advances in our understanding of adipose-derived stromal/stem cells (ASCs) and the utilization of these cells in clinical settings to treat diseases have made it essential to identify the most effective ASCs for therapy. Studies have not yet investigated the impact of obesity on the therapeutic efficacy of ASCs. Obesity is characterized by adipocyte hyperplasia and hypertrophy and can extend to metabolic and endocrine dysfunction. Investigating the impact obesity has on ASC biology will determine whether these cells are suitable for use in regenerative medicine. The therapeutic efficacy of ASCs isolated from lean subjects (body mass index <25; lnASCs) and obese subjects (body mass index >30; obASCs) were determined in murine experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Compared to the EAE disease-modifying effects of lnASCs, obASCs consistently failed to alleviate clinical symptoms or inhibit inflammation in the central nervous system. When activated, obASCs expressed higher mRNA levels of several pro-inflammatory cytokines compared to lnASCs. Additionally, conditioned media collected from the obASCs markedly enhanced the proliferation and differentiation of T cells; whereas, conditioned media from lnASC did not. These results indicate that obesity reduces, or eliminates, the anti-inflammatory effects of human ASCs such that they may not be a suitable cell source for the treatment of autoimmune diseases. The data suggests that donor demographics may be particularly important when identifying suitable stem cells for treatment.

So after tucking into our christmas lunch we may add a few pounds/kilos. What this study does is looks at stem cells from fat cells from fat people and says they don't work unlike stem cells from thin people. This may be because they produce pro-inflammatory factors.

The question is, Is this why we are interested in stem cells?

Don't we want them to repair as there are plenty of treatments to deal with the immune response. Do stem cells do this any better..generally the answer is no.

INTRODUCTION:The important protective role of small heat-shock proteins (HSPs) in regulating cellular survival and migration, counteracting protein aggregation, preventing apoptosis, and regulating inflammation in the central nervous system is now well-recognized. Yet, their role in the neuroinflammatory disorder multiple sclerosis (MS) is largely undocumented. With the exception of alpha B-crystallin (HSPB5), little is known about the roles of small HSPs in disease.RESULTS: Here, we examined the expression of four small HSPs during lesion development in MS, focussing on their cellular distribution, and regional differences between white matter (WM) and grey matter (GM). It is well known that MS lesions in these areas differ markedly in their pathology, with substantially more intense blood-brain barrier damage, leukocyte infiltration and microglial activation typifying WM but not GM lesions. We analysed transcript levels and protein distribution profiles for HSPB1, HSPB6, HSPB8 and HSPB11 in MS lesions at different stages, comparing them with normal-appearing brain tissue from MS patients and non-neurological controls. During active stages of demyelination in WM, and especially the centre of chronic active MS lesions, we found significantly increased expression of HSPB1, HSPB6 and HSPB8, but not HSPB11. When induced, small HSPs were exclusively found in astrocytes but not in oligodendrocytes, microglia or neurons. Surprisingly, while the numbers of astrocytes displaying high expression of small HSPs were markedly increased in actively demyelinating lesions in WM, no such induction was observed in GM lesions. This difference was particularly obvious in leukocortical lesions covering both WM and GM areas.CONCLUSIONS: Since induction of small HSPs in astrocytes is apparently a secondary response to damage, their differential expression between WM and GM likely reflects differences in mediators that accompany demyelination in either WM or GM during MS. Our findings also suggest that during MS, cortical structures fail to benefit from the protective actions of small HSPs.

Heat shock proteins (HSP) are a family of proteins that are produced bycells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including exposure to cold,UV light, and during wound healing or tissue remodeling. Many members of this group perform chaperone function by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by the cell stress. The dramatic upregulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (HSF). In this study they found that some heat shock proteins are increased in astrocytes in the white matter but not the grey matter and not in oligodendrocytes that expressed HSPB5 (alpha B crystallin). So maybe a response to demyelination of white matter axons. So does this mean grey matter lesions do worse?

Using proteomics, we previously identified chromogranin A (CgA) and clusterin (CLU) as disease-related proteins in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS). CgA and CLU are involved in cell survival and are implicated in neurodegenerative disorders and may also have roles in MS pathophysiology. We investigated CgA and CLU expression in lesions and nonlesional regions in postmortem brains of MS patients and controls and in the brains of marmosets with experimental autoimmune encephalomyelitis. By quantitative PCR, mRNA levels of CgA and CLU were elevated in white matter but not in grey matter of MS patients. In situ analyses showed greater expression of CgA and CLU in white matter lesions than in normal-appearing regions in MS patients and in the marmosets, primarily in or adjacent to perivascular spaces and inflammatory infiltrates. Both proteins were expressed by glial fibrillary acidic protein-positive astrocytes. CgA was more localized in astrocytic processes and endfeet surrounding blood vessels and was abundant in the superficial glia limitans and ependyma, 2 CSF-brain borders. Increased expression of CgA and CLU in reactive astrocytes in MS white matter lesions supports a role for these molecules as neuro-inflammatory mediators and their potential as CSF markers of active pathological processes in MS patients.

BACKGROUND:Immunoglobulin G (IgG) effector functions are regulated by the composition of glycans attached to a conserved N-glycosylation site in the Fc part. Intrathecal production of IgG, especially IgG1, is a hallmark of multiple sclerosis (MS), but nothing is known about IgG Fc glycosylation in MS and in cerebrospinal fluid (CSF) in general.

RESULTS:Our experiments revealed four main results. First, IgG1 glycosylation patterns were different in CSF vs. serum, in the MS group and even in control donors without intrathecal IgG synthesis. Second, in MS patients vs. controls, IgG1 glycosylation patterns were altered in CSF, but not in serum. Specifically, in CSF from the MS group, bisecting GlcNAc were elevated, and afucosylation and galactosylation were reduced. Elevated bisecting GlcNAc and reduced galactosylation are known to enhance IgG effector functions. Third, hypothesis-free regression analysis revealed that alterations of afucosylation and bisecting GlcNAc in CSF from MS cases peaked 2-3 months after the last relapse. Fourth, CSF IgG1 glycosylation correlated with the degree of intrathecal IgG synthesis and CSF cell count.

CONCLUSIONS:The CNS compartment as well as the inflammatory milieu in MS affect IgG1 Fc glycosylation. In MS, the CSF IgG1 glycosylation has features that enhance Fc effector functions.

Figure: Astrocytes hold a strategic position in the CNS,
being in close contact to neurons, microglia, oligodendrocytes and other
astrocytes and with blood vessels. Following activation (for instance
during infection), astrocytes secrete factors that activate bystander
cells and increase BBB permeability, resulting in recruitment of immune
cells into the brain.

There is more to the inflammatory process than meets the eye. Meet three of the front line contenders: T and B cells with their global response capability and astrocytes which were initially felt to be gap fillers in the brain neural network, but now are understood to be active players in CNS innate immunity. The astrocytes, however are the only resident myeloid cells in the nervous system, and form a glia limitans around blood vessels restricting access of immune cells to the brain (see figure above).

It is possible that astrocytes are locally activated, as demonstrated in the first abstract with increased expression of both chromogranin and clusterin in MS white matter lesions and not grey matter. This may have something to do with the location of perivascular spaces, which are compartments that surround small blood vessels as they penetrate the brain, and are a site for immune cell accumulation during CNS inflammation.

The B/plasma cells on the other hand, among other things are defined by their antibody production. As I've alluded to in previous blog posts, we do not know what the oligoclonal bands are directed at. Maybe, it doesn't really matter?! In the second abstract, the authors point out that MS CSF contains oligoclonal bands with a glycan pattern that enhances its effector function. It's conceivable that the glycosylation process itself is what makes the unsuspecting immunoglobulin more pro-inflammatory than it intended to be? In fact, this process itself is not unique to MS and has been described in rheumatoid arthritis and neuromyelitis optica. Moreover, they also found that alterations in glycosylation patterns in the CSF occured shortly after a relapse. See a common theme here? As Carl von Clausewitz's famous treatise On War goes: "War is fighting and operates in a peculiar element-danger. But war is served by many activities quite different from it, all of which concern the maintenance of the fighting forces. These preparatory activities are excluded from the narrower meaning of the art of war-the actual conduct of war, because they are concerned only with the creation, training, and maintenance of the fighting forces."

Monday, 28 December 2015

"Can we manage MS using a simple algorithm or flowchart? The review paper below suggests this is possible. I have always been reluctant to formulate algorithms; in my opinion there are simply too many personal decisions that need to be considered when choosing a treatment strategy and/or DMT to make a easy to use algorithm possible. May be I am wrong? Do you think there is a need for an app, powered by an algorithm, to help you make a decision regarding DMTs? I suspect if the app was intelligent enough it could perform as well, if not better, than a neurologist who may have certain biases when it comes to prescribing DMTs."

Treatment options in relapsing-remitting multiple sclerosis have increased considerably in recent years; currently, a dozen different preparations of disease-modifying therapies are available and some more are expected to be marketed soon. For the treating neurologist this broad therapeutic repertoire not only greatly improves individualized management of the disease, but also makes choices more complex and difficult. A number of factors must be considered, including disease activity and severity, safety profile, and patient preference. We here discuss the currently existing options and suggest treatment algorithms for managing relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) patients earn lower incomes and receive higher benefits. However, there is limited knowledge of how this is correlated with their disability.OBJECTIVE:To elucidate sources and levels of income among MS patients with different disability, assessed with the Expanded Disability Status Scale.METHODS: A total of 7929 MS patients aged 21-64 years and living in Sweden in 2010 were identified for this cross-sectional study. Descriptive statistics, logistic and truncated linear regression models were used to estimate differences between MS patients regarding earnings, disability pension, sickness absence, disability allowance, unemployment compensation, and social assistance.RESULTS: The average level of earnings was ten times lower and the average level of health- related benefits was four times higher when comparing MS patients with severe and mild disability. MS patients with severe disability had on average SEK 166,931 (£13, 350) less annual income from earnings and SEK 54,534 (£4,360) more income from benefits compared to those with mild disability. The combined average income for MS patients was 35% lower when comparing patients in the same groups. The adjusted risk ratio for having earnings among MS patients with severe disability compared to the patients with mild disability was 0.33 (95% CI 0.29-0.39), while the risk ratio for having benefits was 1.93 (95% CI 1.90-1.94).CONCLUSIONS:Disease progression affects the financial situation of MS patients considerably. Correlations between higher disability and patient income were observed, suggesting that earnings and benefits could be used as measures of MS progression and proxies of disability.

Whilst Santa may have come from Scandernavia with good news, this is not so good news and shows how MS can affect our capacity to work and as you become more disabled there are higher costs in benefits

Sunday, 27 December 2015

Learn how to practice MSology. #NeuroSpeak #CaseStudy #MSBlog"On my recent trip to New York I was asked why do I contribute to an MS Blog. The reasons are multiple and one important one is education. We are therefore launching a new series of posts in the New Year called 'NeuroSpeak: Case Studies' as a platform to demonstrate to trainee healthcare professionals (HCPs) how to manage MS. The format will be a short case scenario with several questions. The latter will take about 5-10 minutes to complete. This will then be followed-up in ~2 weeks time by a short webinar (10-15 mins) to discuss the questions and to report the survey results. Based on the response of the readers of this blog we have decided not to do these case studies behind a firewall so that people with MS (pwMS) or MSers can also participate. I feel strongly about this as this will demonstrate to you how the 'art of neurology' is practiced and give you some insight into the neurological decision making process. These case studies are part of the evolution of the practice of medicine and will go a long way to helping you self-manage your MS.""The following is the first case study in the series:

Questions you need to consider before the Jan-2016 webinar:

What type of MS does this patient now have (Dec 2015)?

What was his baseline prognostic profile in Feb-2005?

Would you have managed his MS differently?

In Feb-2005?

Between Oct-2006 to May-2012?

Between May-2012 to Dec-2015?

Would you stop his glatiramer acetate (Dec-2015)?

Does knowing his EDSS profile help you clinically?

Excluding symptomatic treatments how would you manage his MS in 2016?"

BACKGROUND:Exposure to parental chronic illness is associated with adverse developmental outcomes.OBJECTIVE:We examined the association between parental multiple sclerosis (MS) and parental MS-related clinical factors on developmental health.METHODS:We conducted a population-based cohort study in British Columbia, Canada, using linked health databases. The outcome was childhood development at 5 years of age, expressed as vulnerability on the Early Development Instrument (EDI).RESULTS: MS-affected parents (n = 783) were older, more likely to be English speakers, and had higher rates of mental health morbidity (39.6% vs 22.2%, p < 0.001) than unaffected parents (n = 2988). Children of mothers with MS (aOR = 0.62, 95% CI = 0.44-0.87), but not children of the fathers with MS, had a lower risk of vulnerability on the social development domain of the EDI. However, mental health comorbidity (aOR = 1.62, 95% CI = 1.05-2.50) and physical comorbidity (aOR = 1.67, 95% CI = 1.05-2.64) among mothers with MS were associated with increased vulnerability on the EDI.

CONCLUSION: Maternal MS, but not paternal MS, was associated with lower rates of developmental vulnerability on the social development domain. However, mental and physical comorbidity among MS-affected mothers were associated with increased developmental vulnerability in children.

The Early Development Instrument is a validated, population-based measure of early child development in five key domains (physical health, emotional maturity, social competence, language and cognitive skills, and communications skills and general knowledge). So what does this say? That if you look at children of parents with MS and mums make the difference and if mums are doing badly there are more risk of influneces on the children.

Multiple sclerosis (MS) is mediated primarily by autoreactive T cells. However, evidence suggesting the involvement of humoral immunity in brain diseases has increased interest in the role of B cells and their products during MS pathogenesis. The major survival factor for B cells, BAFF has been shown to play a role in several autoimmune conditions. Elevated BAFF levels have been reported in MS animal model and during MS relapse in patients. Moreover, disease-modifying treatments (DMT) reportedly influence blood BAFF levels in MS patients, but the significance of these changes remains unclear. The present study addresses how blood BAFF levels are associated with the clinical course of relapsing-remitting MS and the effectiveness of DMT and short-term steroid treatment. During a prospective longitudinal follow-up of 2.3 years, BAFF was measured in the blood of 170 MS patients in the stable phase and within 186 relapses. BAFF levels were significantly higher in MS patients compared to healthy controls. However, stable MS patients without relapses exhibited significantly higher BAFF levels than relapsing patients. Treatment with interferon-β and immunosuppressants raised BAFF blood levels. Interestingly, a similar effect was not seen in patients treated with glatiramer acetate. Short-term treatment with high doses of intravenous methylprednisolone did not significantly alter plasma BAFF levels in 65% of relapsing-remitting MS patients. BAFF were correlated weakly but significantly with monocyte and basophil counts, but not with other blood cell types (neutrophils, lymphocytes, or eosinophils) or inflammatory biomarkers. To our knowledge, this is the first report demonstrating that higher blood BAFF levels may reflect a more stable and effective MS treatment outcome. These results challenge hypotheses suggesting that elevated blood BAFF levels are associated with more severe disease presentation and could explain the recent failure of pharmaceutical trials targeting BAFF with soluble receptor for MS treatment.Sad thing is no one witl go near BAFF as a target as it made MS worse.

BACKGROUND:Multiple Sclerosis (MS) is a neurological disease in which demyelination and axonal loss leads to progressive disability. Cognition impairment is among the most common complication. Studying axonal loss in the retina is a new marker for MS. The main goal of our study is to search for correlations between magnetic resonance imaging (MRI) findings and the retinal nerve fiber layer (RNFL) thickness at the macula and head of the optic nerve and Wechsler Adult Intelligence Scale-Revised (WAIS-R) Scores that assess multiple domains of intelligence, and to explore the relationship between changes in the RNFL thickness with intellectual and cognitive dysfunction.MATERIALS AND METHODS:A prospective cross-sectional study was conducted at the University Hospital of Kashani, Isfahan, Iran, from September to December 2013. All patients were assessed with a full-scale intelligence quotient (IQ) on the WAIS-R. An optical coherence tomography study and brain MRI were performed in the same week for all the patients. Statistical analysis was conducted by using a bivariate correlation, by utilizing SPSS 20.0. A P value ≤ 0.05 was the threshold of statistical significance.RESULTS:Examination of a 100 patients showed a significant correlation between the average RNFL thickness of the macula and the verbal IQ (P value = 0.01) and full IQ (P value = 0.01). There was a significant correlation between brain atrophy and verbal IQ.CONCLUSION:The RNFL loss was correlated with verbal IQ and full IQ.

We have been here before, does problems in the eye correlate with changes in the brain, yes the more brain lesions the greater chance you have eye problems is there an absolute correlation NO, if you have eye problems it does not mean you have brain problems and if you have brain problems it does not mean you will have eye problems...How many more papers on this subject matter? Loads I suspect

We (DrK) have a project on trying to develop cladribine for people with MS as we believe that it has value as a DMT that is effective, relatively safe, convenient, CNS penetrant to target disease activity, and cost-effective (CLICK).ProfG led on this with Merck for the commercial product (Movectro) that was licenced in Australia and Russia in 2010Since the cessation of commercial interest in 2011, DrK has been leading (as ProfG was conflicted due to his involvement with Merck) the exploration of whether generic cladribine can play a part in the treatment of MS. With re-newed interest in Movectro and a new Licence application to the EMA, development of generic cladribine for relapsing MS in Europe, became un-realistic (See the story below). However, their is still value in exploring generic cladribine. Why develop Cladribine? (CLICK HERE). New posts can be found here. BartsMS Off-label Use of Cladribine. Information documentsBartsms-off-label-cladribine-use.html

Thursday, 24 December 2015

Is the ability of EBV to infect neurons relevant to MS? #ResearchSpeak #MSBlog #MSResearch

"One of the problems with the EBV hypothesis of MS is how does it explain some of the clinical observations we see, for example the treatment effect of natalizumab and other anti-trafficking drugs such as fingolimod, and the rebound that occurs when these drugs are stopped? I have previously discussed the field hypothesis, i.e. that a virus may infect glial or neuronal cells that are hidden from the immune system by natalizumab and that when you stop natalizumab the immune system finds the virus and causes rebound. However, this does not explain why MSers don't get symptoms from the viral infection of the glial and/or neuronal cells in the absence of an immune response. This is the flaw in the field hypothesis."

"The study below shows that gamma herpes viruses, including EBV, can infect neuronal cells, with lytic infection (a type of infection that kills the cell). If this is how EBV causes MS it would almost certainly cause symptoms (relapses), or disease progression (worsening), in MSers on natalizumab of fingolimod. The latter does not appear to happen at least in the short to intermediate term. In addition, when we and others have looked at which cells express EBV in the brains of people with MS it does not appear to be neurons, but B cells. Therefore, I am not sure what to make of the conclusions of the study below and whether or not these observations are relevant to MS. Clearly more work needs to be done on this to see if it is relevant to MS and other disease models. Which disease model you may ask? The best model of MS happens to be the Japanese Macaque Encephalomyelitis model that happens to be caused by a gamma herpesvirus."

Background: Gammaherpesviruses human herpesvirus 4 (HHV4) and HHV8 are two prominent members of the herpesvirus family associated with a number of human cancers. HHV4, also known as Epstein-Barr virus (EBV), a ubiquitous gammaherpesvirus prevalent in 90 to 95% of the human population, is clinically associated with various neurological diseases such as primary central nervous system lymphoma, multiple sclerosis, Alzheimer’s disease, cerebellar ataxia, and encephalitis. However, the possibility that EBV and Kaposi’s sarcoma-associated herpesvirus (KSHV) can directly infect neurons has been largely overlooked.

Methods & Results: This study has, for the first time, characterized EBV infection in neural cell backgrounds by using the Sh-Sy5y neuroblastoma cell line, teratocarcinoma Ntera2 neurons, and primary human fetal neurons. Furthermore, we also demonstrated KSHV infection of neural Sh-Sy5y cells. These neuronal cells were infected with green fluorescent protein-expressing recombinant EBV or KSHV. Microscopy, genetic analysis, immunofluorescence, and Western blot analyses for specific viral antigens supported and validated the infection of these cells by EBV and KSHV and showed that the infection was efficient and productive. Progeny virus produced from infected neuronal cells efficiently infected fresh neuronal cells, as well as peripheral blood mononuclear cells. Furthermore, acyclovir was effective at inhibiting the production of virus from neuronal cells similar to lymphoblastoid cell lines; this suggests active lytic replication in infected neurons in vitro. These studies represent a potentially new in vitro model of EBV- and KSHV-associated neuronal disease development and pathogenesis.

Importance: To date, no in vitro study has demonstrated gammaherpesvirus infection of neuronal cells. Moreover, worldwide clinical findings have linked EBV to neuronal pathologies, including multiple sclerosis, primary central nervous system lymphoma, and Alzheimer’s disease. In this study, for the first time, we have successfully demonstrated the in vitro infection of Sh-Sy5y and Ntera2 cells, as well as human primary neurons. We have also determined that the infection is predominately lytic. Additionally, we also report infection of neuronal cells by KSHV in vitro similar to that by EBV. These findings may open new avenues of consideration related to neuronal pathologies and infection with these viruses. Furthermore, their contribution to chronic infection linked to neuronal disease will provide new clues to potential new therapies.

OBJECTIVE:The temporal relationship between white matter (WM) and gray matter (GM) damage in vivo in early primary progressive multiple sclerosis (PPMS) was investigated testing 2 hypotheses: (1) WM tract abnormalities predict subsequent changes in the connected cortex ("primary WM damage model"); and (2) cortical abnormalities predict later changes in connected WM tracts ("primary GM damage model").METHODS:Forty-seven patients with early PPMS and 18 healthy controls had conventional and magnetization transfer imaging at baseline; a subgroup of 35 patients repeated the protocol after 2 years. Masks of the corticospinal tracts, genu of the corpus callosum and optic radiations, and of connected cortical regions, were used for extracting the mean magnetization transfer ratio (MTR). Multiple regressions within each of 5 tract-cortex pairs were performed, adjusting for the dependent variable's baseline MTR; tract lesion load and MTR, spinal cord area, age, and sex were examined for potential confounding.RESULTS:The baseline MTR of most regions was lower in patients than in healthy controls. The tract-cortex pair relationships in the primary WM damage model were significant for the bilateral motor pair and right visual pair, while those in the primary GM damage model were only significant for the right motor pair. Lower lesion MTR at baseline was associated with lower MTR in the same tract normal-appearing WM at 2 years in 3 tracts.CONCLUSION: These results are consistent with the hypothesis that in early PPMS, cortical damage is for the most part a sequela of normal-appearing WM pathology, which, in turn, is predicted by abnormalities within WM lesions.

So this study asks in PPMS what happens first, white matter damage? or grey matter damage?. They think that the white matter damage results in subsequent grey matter damage, but if I chop a nerve in two you would them expect the nerve cell body to reflect this a bit later. The sad thing is that these PPMSers are just been watched and not treated.However what do other people thing so another group get on their magnet and what do they find the chicken, egg or the turkey?Steenwijk MD, Geurts JJ, Daams M, Tijms BM, Wink AM, Balk LJ, Tewarie PK, Uitdehaag BM, Barkhof F, Vrenken H, Pouwels PJ.Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant Brain. 2015. pii: awv337. [Epub ahead of print]

Grey matter atrophy is common in multiple sclerosis. However, in contrast with other neurodegenerative diseases, it is unclear whether grey matter atrophy in multiple sclerosis is a diffuse 'global' process or develops, instead, according to distinct anatomical patterns. Using source-based morphometry we searched for anatomical patterns of co-varying cortical thickness and assessed their relationships with white matter pathology, physical disability and cognitive functioning. Magnetic resonance imaging was performed at 3 T in 208 patients with long-standing multiple sclerosis(141 females; age = 53.7 ± 9.6 years; disease duration = 20.2 ± 7.1 years) and 60 age- and sex-matched healthy controls. Spatial independent component analysis was performed on cortical thickness maps derived from 3D T1-weighted images across all subjects to identify co-varying patterns. The loadings, which reflect the presence of each cortical thickness pattern in a subject, were compared between patients with multiple sclerosis and healthy controls with generalized linear models. Stepwise linear regression analyses were used to assess whether white matter pathology was associated with these loadings and to identify the cortical thickness patterns that predict measures of physical and cognitive dysfunction. Ten cortical thickness patterns were identified, of which six had significantly lower loadings in patients with multiple sclerosis than in controls: the largest loading differences corresponded to the pattern predominantly involving the bilateral temporal pole and entorhinal cortex, and the pattern involving the bilateral posterior cingulate cortex. In patients with multiple sclerosis, overall white matter lesion load was negatively associated with the loadings of these two patterns. The final model for physical dysfunction as measured with Expanded Disability Status Scale score (adjusted R2 = 0.297; P < 0.001) included the predictors age, overall white matter lesion load, the loadings of two cortical thickness patterns (bilateral sensorimotor cortex and bilateral insula), and global cortical thickness. The final model predicting average cognition (adjusted R2 = 0.469; P < 0.001) consisted of age, the loadings of two cortical thickness patterns (bilateral posterior cingulate cortex and bilateral temporal pole), overall white matter lesion load and normal-appearing white matter integrity. Although white matter pathology measures were part of the final clinical regression models, they explained limited incremental variance (to a maximum of 4%). Several cortical atrophy patterns relevant for multiple sclerosis were found. This suggests that cortical atrophy in multiple sclerosis occurs largely in a non-random manner and develops (at least partly) according to distinct anatomical patterns. In addition, these cortical atrophy patterns showed stronger associations with clinical (especially cognitive) dysfunction than global cortical atrophy.

So in this study they say white matter is not really the story and they find grey matter damage in certain regions

However maybe you can go abit further and rather than rely on MRI outcomes were we are not 100% certain what they mean and actually do some histology and actually trace the paths of the nerves. Abit of histology will tell you exactly where the grey matter lesions are.

Grey matter pathology has emerged as an important contributor to long-term disability in multiple sclerosis. To better understand where and how neuronal damage in the grey matter is initiated, we used high resolution confocal microscopy of Golgi-Cox impregnated tissue sections and reconstructed single cortical projection neurons in autopsies from eight patients with long-standing relapsing-remitting or secondary progressive multiple sclerosis and eight control patients without neurological disease. Analysis of several hundred individual neurons located in the insular, frontotemporal and occipital lobe revealed a widespread and pronounced loss of dendritic spines in multiple sclerosis cortex that occurs independent of cortical demyelination and axon loss. The presence of a primary synaptic pathology in the normal-appearing cortex of multiple sclerosis patients challenges current disease concepts and has important implications for our understanding of disease progression.

So here they find that it is the synaptic processess in the the cortex that go before demyelination or axonal damage, is this the white matter problem thats causing this? or is this the primary pathology

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